The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes (LT's). Similarly 12- and 15-lipoxygenase, convert arachidonic acid to 12- and 15-HPETE respectively. Biochemical reduction of 12-HPETE leads to 12-HETE, while 15-HPETE is the precursor of the class of biological agents known as the lipoxins.
A variety of biological effects are associated with these products from lipoxygenase metabolism of arachidonic acid and they have been implicated as mediators in various disease states. For example, the LTC.sub.4 and LTD.sub.4 are potent constrictors of human airways in vitro and aerosol administration of these substances to non-asthmatic volunteers induces broncho-constriction. LTB.sub.4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also have been found in the synovial fluid of rheumatoid arthritic patients. The biological activity of the leukotrienes has been reviewed by Lewis and Austin (J. Clinical Invest. 73, 889, 1984) and by Sirois (Adv. Lipid Res. 21, 78, 1985).
Thus, lipoxygenase enzymes play an important role in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, inflammatory bowel disease, gout, adult respiratory distress syndrome, endotoxin shock and inflammation. Blocking these enzymes interrupts the biochemical pathways involved in these disease states.